PROJECT SUMMARY/ABSTRACT Human facial morphology varies both within and among populations, and this variation is driven in large part by genetic factors. Over the past seven years, gene mapping studies have identified numerous chromosomal regions associated with normal-range facial variation. Using advanced methods of biological shape analysis, our group recently uncovered over 200 such regions. Despite our success, these signals collectively explain only a small fraction of the heritable variation in facial shape, suggesting that much of the genetic architecture underlying human facial shape is yet to be discovered. A more complete understanding of this genetic architecture may provide insights into the mechanisms that control how the human face forms, offer insights into the etiology of craniofacial syndromes and birth defects, and eventually lead the way toward genetically- informed personalized therapeutic interventions for craniofacial surgery and orthodontics. Critically, we also lack knowledge about which genetic variants are functionally active at the implicated chromosomal regions or which genes they even target, limiting our ability to design future studies to sort out the biological mechanisms involved in building faces. The current proposal has three aims designed to significantly advance our understanding of human facial genetics: (1) we will perform a series of high-throughput experiments designed to delineate functional variants from our gene-mapping studies that drive craniofacial gene expression; (2) we will leverage new sources of data to bolster the statistical power of our gene-mapping efforts, paving the way for the discovery of new genetic pathways and a deeper understanding of the complex genetic networks and interactions that underlie variation in facial features; and (3) by applying innovative image processing and morphometric modeling techniques, we will utilize a large longitudinal dataset of over 11,000 adolescents with genetic markers and craniofacial images available at multiple timepoints to scan the genome for variants that impact key aspects of facial growth, such as timing of maturation and rate of change. Understanding the genetic basis of these growth traits has potential clinical relevance for fields like craniofacial surgery and orthodontics, where an individual?s facial growth trajectory can be an important factor in personalized treatment planning. By connecting genotypes to facial phenotypes and subsequently delineating functional variants, this project promises to fill gaps in our knowledge about the genetic basis of human facial traits and offer novel insights into the molecular mechanisms underlying both normal and abnormal facial development.